Urenna Orazulike

Introduction: An ischemic stroke occurs when blood circulation to the brain is reduced or blocked, such that cerebral neurons are deprived of oxygen and nutrients.¹ Brain edema forms soon after the onset of vascular blockage and the ensuing interruption in cerebral blood flow. Recent studies have discovered that waste clearance in the central nervous system takes place via the “glymphatic (glial-lymphatic) system”³ which directs movement of CSF via active transport from para-arterial spaces to paravenous spaces, facilitated by aquaporin-4 (AQP4) channels located in the end feet of astrocytes.^2,3 Increased CSF pressure causes its egresses to cervical lymph nodes external to the brain, via the final part of the glymphatic pathway – the perineural sheaths in the cribriform plate. In the first 24-48 hours following ischemic insult, there is abnormal transportation of water and ions into injured neurons (particularly astrocytes), resulting in cytotoxic swelling.^2,  72-96 hours post-infarct, damage extends to the blood-brain barrier and there is an increase in permeability of substances coming in from vasculature, causing vasogenic edema. Lack of treatment options and a narrow therapeutic window highlights the need for research that delineates the underlying mechanisms and pathology surrounding cerebral edema, and novel therapies that target the major players involved. Methods & Results: To better understand the effect of AQP modulation in edema, experiments on animal models were conducted to derive a new CSF tracer (oxygen-17 labeled water) that provided a more efficient and accurate means of imaging glymphatic water transport in the brain. AQP4 inhibitor TGN-020 was used to pretreat a group of rats. Results confirmed that a smaller molecule like oxygen-17 labeled water) would be a better candidate than the heavy-weight Gd-DTPA tracer molecule previously used as standard. For the vasogenic stage, a potential therapy being explored is the use of intra-arterial 1×10⁵ mesenchymal stem cells (IA MSCs) and experiments were conducted on mice to demonstrate the effects of PKCδ-modulated IA MSC activity on AQP4 expression. Results show that administration of “IA MSC’s+ doxy” had the highest reduction in all of the pathogenic criteria evaluated. Additionally, CSF tracer injected into the subarachnoid compartments was observed in perineural spaces of the olfactory nerves and submucosal tissue 3 and 24 hours after tracer injection, confirming cribriform plate as a major CSF outflow site. Conclusion: Communication between the brain’s internal glymphatic system and its neighboring external lymphatic system provides a novel therapeutic interface in post-ischemic stroke patients.

1. Alshuhri MS, Gallagher L, Work LM, Holmes WM. Direct imaging of glymphatic transport using H217O MRI. JCI Insight. 2021;6(10):e141159. Published 2021 May 24. doi:10.1172/jci.insight.141159
2. Rasmussen JC, Kwon S, Pinal A, et al. Assessing lymphatic route of CSF outflow and peripheral lymphatic contractile activity during head-down tilt using near-infrared fluorescence imaging. Physiol Rep. 2020;8(4):e14375. doi:10.14814/phy2.14375
3. Datta A, Sarmah D, Kaur H, et al. Post-stroke Impairment of the Blood-Brain Barrier and Perifocal Vasogenic Edema Is Alleviated by Endovascular Mesenchymal Stem Cell Administration: Modulation of the PKCδ/MMP9/AQP4-Mediated Pathway [published online ahead of print, 2022 Feb 21]. Mol Neurobiol. 2022;10.1007/s12035-022-02761-2. doi:10.1007/s12035-022-02761-2
4. Ringstad G, Eide PK. Cerebrospinal fluid tracer efflux to parasagittal dura in humans. Nat Commun. 2020;11(1):354. Published 2020 Jan 17. doi:10.1038/s41467-019-14195-x
5. Ma Q, Ineichen BV, Detmar M, Proulx ST. Outflow of cerebrospinal fluid is predominantly through lymphatic vessels and is reduced in aged mice. Nat Commun. 2017;8(1):1434. Published 2017 Nov 10. doi:10.1038/s41467-017-01484-6
6. Ji C, Yu X, Xu W, Lenahan C, Tu S, Shao A. The role of the glymphatic system in the cerebral edema formation after ischemic stroke. Exp Neurol. 2021 Jun; 340:113685. doi: 10.1016/j.expneurol.2021.113685. Epub 2021 Mar 5. PMID: 33676917.